Ischemic stroke is an acute disease where tissue death (infarction) within the brain of different patients will progress at different rates from the time of the ischemic event. The rate of infarction within a patient depends on a large number of physiological factors.
For the physician diagnosing and treating ischemic strokes, when a stroke patient arrives at a hospital, it is very important for the physician to obtain as much knowledge about the nature of the stroke as soon as possible in order to make an effective diagnosis and effective decisions regarding treatment. As is readily understood, time to effect diagnosis and treatment is very important as faster diagnoses will impact treatment decisions and can minimize the amount of brain tissue that is ultimately affected as a result of the stroke.
For example, in the case of an ischemic stroke, it is important for the physician to know where the vessel occlusion is, how big the occlusion is, where any dead brain tissue (termed “core”) is and, how big and where is the brain tissue that may have been affected by the ischemic event but that may potentially be saved (this tissue is termed “penumbra”).
More specifically, the penumbra is tissue around the ischemic event that can potentially stay alive for a number of hours after the event due to perfusion of this tissue by collateral arteries. That is, the collateral arteries may provide sufficient oxygen to the penumbra tissue to prevent this tissue from dying for a period of time.
When the physician has good information about the collaterals and how the collaterals may be located in and around the penumbra, treatment decisions can be made that can significantly affect patient outcomes.
Importantly, in an emergency or acute situation, the process of making a decision will consider the amount of information at a given moment in time. That is, a definitive ‘yes’ decision can be made to take action or a ‘no’ decision can be made to take no action based on the current information. In addition, a third decision choice can be made to wait for additional information. In the situation of acute stroke (and other emergency scenarios), time to make a definitive diagnostic/treatment decision must be balanced against the likelihood of a negative outcome that results simply from the delay in making a decision. In other words, the decision to wait for more information must consider what the effects of a delay in making a decision might be.
In the specific case of acute ischemic stroke, the pace or rate of neural circuitry loss in a typical large vessel supratentorial acute ischemic stroke is shown in Table 1.
TABLE 1Estimated Pace of Neural Circuitry Loss in TypicalLarge Vessel, Supratentorial Acute Ischemic Stroke (3)Estimated Pace of Neural Circuitry Loss in TypicalLarge Vessel, Supratentorial Acute Ischemic StrokeNeuronsSynapsesMyelinatedAcceleratedLostLostFibers LostAgingPer Stroke1.2billion8.3trillion  7140 km/4470 miles36yrsPer Hour120billion830billion    714/447 miles3.6yrsPer Minute1.9million14billion   12 km/7.5 miles3.1weeksPer Second32,000230million200 meters/218 yards8.7hours
As can be seen, delays in making a decision in the order of only a few minutes can have a significant impact on patient outcome in terms of neural circuitry loss. Moreover, and as shown in FIGS. 1 and 2, a better outcome is significantly more likely to occur when the decision to treat is made earlier. As shown in FIG. 1, whether or not a treatment is ultimately beneficial or not may depend on when the decision to treat is made. As shown in FIG. 1, treatment decision times A, B, C, D will each have a different affect on the relative number of neurons that could be saved. That is, if a treatment decision is made at time A (i.e. an earlier time), if it is assumed that the pace of neural circuitry loss is linear (assumed only for this example), a greater number of neurons can be saved. As the time of making the treatment decision is delayed, the likelihood of the treatment being beneficial will decrease until it is uncertain whether the treatment will be beneficial (i.e. at times B and C) or where there is a high likelihood that the treatment will be of no value (i.e. at time D).
Further, FIG. 2 illustrates the effect of time to reperfusion and good clinical outcome for observed cases where the abscissa shows time from stroke to reperfusion and the ordinate shows the probability of the patient achieving a post-treatment mRS score of 0-2. Table 2 shows the time to reperfusion and good clinical outcome for the data of FIG. 2 (1).
TABLE 2Time to Reperfusion and Good Clinical OutcomeRisk Ratio95% CIp-valueTime to Reperfusion0.860.78-0.95P = 0.0045(every 30 minutes)
At the present time, in many treatment centers, when a stroke patient arrives, the assessment protocol is generally as follows:                a. Conduct a CT scan of the head to rule out or look for evidence of a hemorrhagic stroke.        b. Conduct a CT angiogram (CTA) to locate the site of vessel occlusion.        c. Conduct a CT perfusion (CTP) study to create perfusion maps that provide the physician with information about various parameters including cerebral blood flow, cerebral blood volume and mean transit time.        
As is known, each of these generalized steps will be affected by a large number of factors and the time to complete each of them will be variable from patient to patient and between different treatment centers. For example, such factors may include resource availability (eg. trained medical staff and equipment) as well as processing times required by CT scan equipment and other ancillary hardware and software to present data to physicians.
For the purposes of illustration, these factors are described in terms of a representative diagnosis and treatment scenario of a patient exhibiting symptoms of a stroke, the patient arriving at the emergency room of a treatment center and who thereafter receives the above CT procedures as part of the diagnostic protocol. Table 3 summarizes a number of the key process steps and typical times that may be required to complete each step.
Upon arrival at the treatment center, an emergency room physician conducts a preliminary assessment of the patient. If the preliminary assessment concludes a potential stroke, the patient is prepared for a CT scan. The time taken to initially assess a potential stroke patient upon arrival at the treatment facility may be 3-5 minutes.
Preparing the patient for a CT scan involves a number of steps including transferring the patient to the CT imaging suite and connecting an intra-venous line to the patient to enable the injection of contrast agent into the patient during the various CT procedures.
The CT scan includes conducting an x-ray scan of the patient together with a computerized analysis of the x-ray data collected. More specifically, as is known, during a CT scan, beams of x-rays are emitted from a rotating device through the area of interest in the patient's body from several different angles to receivers located on the opposite sides of the body. The received data is used to create projection images, which are then assembled by computer into a two or a three-dimensional picture of the area being studied. More specifically, the computer receives the x-ray information and uses it to create multiple individual images or slices which are displayed to the physician for examination.
CT scans require that the patient hold still during the scan because significant movement of the patient will cause blurred images. This is sometimes difficult in stroke patients and hence sometimes head restraints are used to help the patient hold still. Complete scans take only a few minutes.
Upon completion of the initial CT scan including the post-processing time to assemble the images, the physician interprets the images to determine a) if a stroke has occurred and, b) if so, to determine if the stroke is hemorrhagic or ischemic. If the stroke is hemorrhagic, different procedures may be followed. It will typically take the physician in the order of 1-2 minutes from the time the images are available to make the determination that the stroke is hemorrhagic or ischemic.
If the stroke is ischemic, the decision may be made to conduct a CT angiogram (CTA).
CT angiography procedures generally require that contrast agents be introduced into the body before the scan is started. Contrast is used to highlight specific areas inside the body, in this case the blood vessels. In addition because of presence of contrast in the very small vessels of the brain, overall the brain looks brighter (has a higher Hounsfield value) also known as contrast enhancement. Contrast agents are iodine based compounds that inhibit the passage of x-rays through the tissue. As such, they can be effective in enhancing the distinction between tissues where the contrast agent is present compared to those tissues where it is not. The CT angiogram requires additional preparation time but will typically not require that the patient be moved. Generally, CT angiogram procedures involve the injection of a bolus of contrast through an IV line followed by the CT scan. A typical contrast bolus may be 70-100 ml injected at 5 ml/second. The volume and injection rate of contrast is determined by the procedure being followed and is generally injected in a minimally sufficient volume to be present in the tissues of interest at the time the CT scan is conducted. Over a relatively short time period, the contrast becomes diffused within the body thereby providing only a relatively short window of time to conduct a CT procedure.
The CT angiogram data is substantially greater than what is collected from a basic scan and like a basic CT scan must be subjected to post-processing to create the images. The post-processing time is typically in the range of 3-5 minutes.
After processing, the physician interprets the data and makes a decision regarding treatment. Generally, the physician is looking to determine a) where is the occlusion? b) what is the size of the core? and c) obtain a qualitative feel for penumbra and collaterals.
Ultimately, and based on these factors, the physician is looking to make a decision on what brain tissue is worth fighting for. In other words, based on the combination of all these factors, the physician is looking to decide either that very little or no penumbra can be saved, or alternatively that it appears that penumbra can be saved and it is worthwhile to do so.
The CT angiogram provides relatively little data about collaterals and perfusion to the ischemic tissue as it is only a picture of the brain at one instance in time. That is, as it takes time for contrast agent to flow through the brain tissues and such flow will be very dependent on the ability of vessels to carry the contrast agent, a single snapshot in time does not give the physician enough information to make a diagnostic and/or treatment decision. Hence, CT perfusion (CTP) procedures may be undertaken to give the physician a more quantitative sense of brain perfusion. Like CT angiogram, CT perfusion procedures involve the injection of contrast agent into the patient. It should also be noted that some centers may choose to do a CT perfusion study before the CT angiogram because they feel that the contrast injection from the CT angiogram interferes with the quality of data of the CT perfusion.
Perfusion computed tomography (CTP) allows qualitative and quantitative evaluation of cerebral perfusion by generating maps of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). The technique is based on the central volume principle (CBF=CBV/MTT) and requires the use of complex software employing complex deconvolution algorithms to produce perfusion maps. Other maps such as Tmax maps may also be created.
CTP studies are acquired with repeated imaging through the brain while the contrast is injected. The technique varies significantly from vendor to vendor and also from center to center and hence requires specialized training with the specific equipment at each center. CTP typically involves imaging of the brain over approximately 60-70 seconds (at 1-4 second intervals) in order to acquire multiple images. The technique is quite vulnerable to patient motion and also requires the patient to hold still for the period. Furthermore, CTP also involves substantial radiation exposure in the range of 5-10 mSv as the number of images taken over the time period is significant.
The procedure generates a large dataset that must then be transferred to a dedicated workstation for post-processing. This step may take over 10 minutes in order to produce separate maps of each of CBF, CBV, and MTT. The perfusion maps are typically color coded maps.
Importantly, the post-processing requires the use of specialized and very often proprietary software that must be run by trained individuals. Ultimately, the time taken to fully complete CTP acquisition and analysis is highly variable as the above factors including the vendor, the speed of data transfer, local expertise, the time of day the study is being undertaken (i.e. working hours vs. after hours) as well as other factors can all have an affect on the actual amount of time required to complete the study.
TABLE 3Typical Diagnostic Steps and Completion TimesTimeElapsedProcedure(minutes)TotalCommentsInitial Assessment3-53-5Transfer and20 23-25Preparation forCT ScanCT Scan124-26CT Scan2-326-30CT Angiogram Prepara-Interpretationtion may be concurrentand CT Angiogramwith CT Scan Interpre-PreparationtationCT Angiogram1-327-33ProcedureCT Angiogram229-35Post ProcessingCT Angiogram433-39CT Perfusion Prepara-Interpretation(minimum)tion may be concurrentand CT Perfusionwith CT Scan Interpre-PreparationtationCT Perfusion134-40ProcedureCT PerfusionVariable 5-20 44-60Will depend on vendorPost Processing(minimum)specificsCT PerfusionVariable 2-10 46-70Will depend factorsInterpretation(minimum)including: time of day;center; vendor equipmentetc.
Thus, while perfusion CT is not a perfect technique, it has been found to be useful for noninvasive diagnosis of cerebral ischemia and infarction as it does provide some degree of quantitative determination of core and penumbra. However, as noted above, there are problems with these procedures. In summary, these problems include:                a. CT perfusion takes time to complete (8-30+ minutes total).        b. Patient motion can affect results.        c. Significant post-processing time is required to complete a full perfusion map.        d. Additional radiation exposure to the patient.        e. Need for additional contrast agents.        f. Non-standardized procedures for completing the perfusion map.        g. Variations in technique with different vendor equipment.        h. Lack of consensus in the medical community regarding the interpretation and best practices for treatments based on the CT perfusion maps.        i. Lack of information regarding rate of infarct growth.        j. Significant variability across vendors for the degree of coverage of the brain (eg. 4 to 16 cms). Also some vendors have the option of covering 8 cm using a ‘toggle table’ technique that may introduce additional errors.        
As a result, notwithstanding the benefits of CTP, there continues to be a need for improved procedures and systems that can address these problems that provide the physician with the ability to make faster diagnoses. Most importantly, there has been a need for improved systems for assessing patient collaterals after ischemic stroke and, in particular, the need to create a fast and reproducible collateral map as opposed to a perfusion map. Further still, there has been a need for systems and methods that enable faster recanalization in order to increase the chances of saving penumbra tissue given the rate of neural death in a typical large vessel ischemic stroke.
In addition, there has also been a need for systems and methods that can be consistently implemented at different treatment centers and across different CT machines (i.e. from different vendors) that reduce the level of specialized and/or advanced training that may be required to provide a consistent and accurate diagnosis.
Further still, there has also been a need for systems and methods that enable the identification and quantification of parameters about the blood clot/thrombus causing an ischemic stroke. That is, in proximal artery occlusion it is helpful to the endovascular surgeon to understand more about the nature of the clot causing the stroke and more specifically know the exact length of the clot and its relative permeability and/or porosity which will aid in treatment decisions.
With regards to hemorrhagic strokes, there is similarly a need for systems and systems methods that enable faster diagnoses with enough information to assist in making treatment decisions.
ASPECTS
In addition, in recent years, stroke physicians have been utilizing a semi-quantitative method for determining the amount of dead brain during the diagnostic processes of ischemic stroke. ASPECTS (Alberta Stroke Program Early CT Score) is a 10 point scoring system that allows physicians utilize to provide a graded score on the relative severity of a stroke. Generally, the lower the ASPECTS score, the greater the severity of the stroke in terms of the amount of dead brain whereas a higher score indicates less brain tissue has died. A more detailed explanation of the ASPECTS system can be found at www.aspectsinstroke.com (incorporated herein by reference). In the context of this description, ASPECTS is defined as the accepted protocol as of the filing date of this application (4).
Generally, ASPECTS was developed to offer the reliability and utility of a standard CT examination with a reproducible grading system to assess early ischemic changes on pretreatment CT studies in patients with acute ischemic stroke of the anterior circulation. It is determined from evaluation of two standardized regions of the MCA territory: the basal ganglia level, where the thalamus, basal ganglia, and caudate are visible, and the supraganglionic level, which includes the corona radiata and centrum semiovale using non-contrast CT data. All cuts with basal ganglionic or supraganglionic structures visible are required to determine if an area is involved. The abnormality should be visible on at least two consecutive cuts to ensure that it is truly abnormal rather than a volume averaging effect
To compute the ASPECTS, 1 point is subtracted from 10 for any evidence of early ischemic change for each of the defined regions. A normal CT scan receives ASPECTS of 10 points and a score of 0 indicates diffuse involvement throughout the MCA territory.
Axial NCCT images showing the MCA territory regions as defined by ASPECTS. C—Caudate, I—Insularribbon, IC—Internal Capsule, L—Lentiform nucleus, M1—Anterior MCA cortex, M2—MCA cortex lateral to the insular ribbon, M3—Posterior MCA cortex, M4, M5, M6 are the anterior, lateral and posterior MCA territories immediately superior to M1, M2 and M3, rostral to basalganglia. Subcortical structures are allotted 3 points (C, L, and IC). MCA cortex is allotted 7 points (insular cortex, M1, M2, M3, M4, M5 and M6)
As noted, ASPECTS is an important method of standardizing or grading the severity of a stroke and over the past number of years has become accepted as the standard by which stroke physicians communicate about the relative severity of strokes. It has been used effectively in recent trials and also as a means of selecting patients for trials to the extent that the guidelines for stroke care have changed across the world. For example, in the United States, guidelines state that, amongst other factors, patients with an ASPECTS score greater than 5 are suitable candidates for endovascular treatment
The method of determining an ASPECTS score is somewhat subjective in that it relies of the qualitative assessment made by one or more physicians based on empirical data. Analysis of the various errors sources of error can be generally categorized into imaging quality errors and interpretation errors.
In the case of imaging errors, factors including the age and nature of the scanning equipment, set-up and operation (eg. radiation levels) can affect the images and hence their interpretation. Also, imaging errors can be a result of patient errors include factors such as patient movement, the presence of old infarcts, age of the patient and related factors such atrophy and microangiopathic disease can also affect interpretation.
Image interpretation can be affected by a lack of adequate training including the availability of expertise at a particular facility as well as the pressure physicians may be under during an emergency and the speed with which decisions may be made.
Recently, there have been attempts to reduce the subjectivity factors in image interpretation through the use of computer algorithms to provide an ASPECTS score from images. A prior art system (Brainomix, Oxford, UK) provides a software system that automates the ASPECTS score from non-contrast CT data. However, at the present time, there is not acceptance that the ASPECTS scores that this software provides are equally or more reliable than physician determined ASPECTS.
That is, there is criticism of this system on the basis that it is not capable of discerning whether the images it is assessing are acceptable images and hence, it will make a determination that does not properly address the quality of the data it is using to make a decision. Importantly, the Brainomix system does not utilize the contribution of collaterals to ASPECTS.
As such many such automated algorithms lack precision and/or specificity e.g. depending on the situation especially in a patients presenting very early, an automated software may be able to say that the ASPECTS is somewhere between 4 to 8: this range is such that it does not permit good decision making (following the American Guidelines). Alternatively the software may be able to calculate (depending on how the algorithm is set up) ASPECTS to state e.g. ASPECTS score of 7 with 60% precision. This again would not allow for good and efficient decision making.
Accordingly, there has been a need for systems and methods that more accurately and more reliably can automate ASPECTS and that utilize the contribution of collateral blood flow to ASPECTS.
Further, biologically it makes sense that poor collaterals will correlate to poorer ASPECTS, since it is blood flow through the collaterals that keep the brain alive.
Based on the pathophysiology and experience, the ASPECTS grading and the collateral grading go hand in hand. There are very few exceptions. These include the situation where the patient is being imaged very quickly after stroke onset where the images show poor collaterals but brain changes (i.e death) hasn't set in yet. Another situation is the patient who at some time went into hypotension/shock before reaching the imaging suite with the result being that the blood supply dropped, the brain died meaning that a poor ASPECTS should be assessed, but prior to subsequent imaging, the blood pressure improved so that by the time the imaging was completed, the collaterals were strong.
As a result, there has been a need for improved systems and methods to automatically calculate ASPECTS with improved accuracy and confidence and more specifically utilizes collateral data.